1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones and 1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones as PDE1 Inhibitors

ABSTRACT

The present invention provides 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones and 1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-ones of formula (I) as PDE1 inhibitors and their use as a medicament, in particular for the treatment of neurodegenerative disorders and psychiatric disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to Danish Patent Application No.PA201600221 (filed: Apr. 12 2016), which application is hereinincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides compounds that are PDE1 enzyme inhibitorsand their use as a medicament, in particular for the treatment ofneurodegenerative disorders and psychiatric disorders.

The present invention also provides pharmaceutical compositionscomprising compounds of the invention and methods of treating disordersusing the compounds of the invention.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signaling. The catalytic activities of PDEs providefor breakdown of cNs over a spectrum of cN-concentrations in all cells,and their varied regulatory mechanisms provide for integration andcrosstalk with myriad signaling pathways. Particular PDEs are targetedto discrete compartments within cells where they control cN level andsculpt microenvironments for a variety of cN signalosomes (Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol. Rev 2011, 91:651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca²⁺-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, PDE1 represents an interesting regulatory link betweencyclic nucleotides and intracellular Ca²⁺. The PDE1 family is encoded bythree genes: PDE1A (mapped on human chromosome 2q32), PDE1B (humanchromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They havealternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain that contains two Ca²⁺/CaMbinding domains and two phosphorylation sites differentiate theircorresponding proteins and modulate their biochemical functions. PDE1 isa dual substrate PDE and the PDE1C-subtype has equal activity towardscAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1B have apreference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignaling pathways, preferably in the nervous system and PDE1 inhibitorscan enhance the levels of the second messengers cAMP/cGMP leading tomodulation of neuronal processes and to the expression of neuronalplasticity-related genes, neurotrophic factors, and neuroprotectivemolecules. These neuronal plasticity enhancement properties togetherwith the modulation of synaptic transmission make PDE1 inhibitors goodcandidates as therapeutic agents in many neurological and psychiatricconditions. The evaluation of PDE1 inhibitors in animal models (forreviews see e.g. Blokland et al. Expert Opinion on Therapeutic Patents(2012), 22(4), 349-354; and Medina, A. E. Frontiers in Neuropharmacology(2011), 5 (Feb.), 21) have suggested the potential for the therapeuticuse of PDE1 inhibitors in neurological disorders, like e.g. Alzheimer's,Parkinson's and Huntington's Diseases and in psychiatric disorders likee.g. Attention Deficit hyperactivity Disorder (ADHD), restless legsyndrome, depression, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS). There have also beenpatent applications claiming that PDE1 inhibitors are useful in diseasesthat may be alleviated by the enhancement of progesterone-signaling suchas female sexual dysfunction (e.g. WO 2008/070095).

WO 2008/139293 and WO 2010/084438 (Pfizer Inc.) and WO 2004/099211(Bayer AG) disclose 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones asPDE9 inhibitors.

The compounds of the invention may offer alternatives to currentmarketed treatments for neurodegenerative and/or psychiatric disorders,treatments which are not efficacious in all patients. Hence, thereremains a need for alternative methods of treatment.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and neurodegenerative disorders.

The objective of the present invention is to provide compounds that arePDE1 inhibitors, and as such are useful to treat neurodegenerativedisorders and psychiatric disorders. Preferably, said compounds are atleast a ten-fold stronger as PDE1 inhibitors than as PDE9 inhibitors inorder to prevent potentially unwanted effects associated with PDE9inhibition.

Accordingly, the present invention relates to compounds of formula (I)

wherein

Y is N or CH;

R₁ is selected from the group consisting of linear or branched C₂-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl and tetrathydropyranyl; all of which can besubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano ormethoxy;R₂ is selected from the group consisting of, linear or branched C₁-C₈alkyl, phenyl, benzo[1,3]dioxole and saturated monocyclic C₃-C₈cycloalkyl; orR₂ is phenyl substituted one or more times with one or more substituentsselected from the group consisting of halogen, C₁-C₃ alkyl and methoxy;orR₂ is pyridinyl substituted with a substituent selected from the groupconsisting of halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkoxy,C₃-C₄ cycloalkoxy and C₄-C₅ methylcycloalkoxy; orR₂ is selected from the group consisting of 5-membered heteroarylssubstituted with C₁-C₃ alkyl;R₃ is selected from the group consisting of linear or branched C₁-C₃alkyl and saturated monocyclic C₃-C₈ cycloalkyl; which can each beoptionally substituted with a substituent selected from halogen, C₁-C₃alkoxy, phenyl, dialkylamine and oxetane; and tautomers andpharmaceutically acceptable salts thereof.

Reference to Compound (I) includes the free base of Compound (I),pharmaceutically acceptable salts of Compound I, such as acid additionsalts of Compound (I), racemic mixtures of Compound (I), or thecorresponding enantiomer and/or optical isomer of Compound I, andpolymorphic and amorphic forms of Compound (I) as well as tautomericforms of Compound (I). Furthermore, the compounds of this invention mayexist in unsolvated as well as in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like. In general, thesolvated forms are considered equivalent to the unsolvated forms for thepurposes of this invention.

In one embodiment, the invention relates to a compound according toformula (I) for use in therapy.

In one embodiment, the invention relates to a compound according toformula (I), for use in the treatment of a neurodegenerative disorder,selected from the group consisting of Alzheimer's Disease, Parkinson'sDisease and Huntington's Disease or for the treatment of a psychiatricdisorder such as Attention Deficit hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS), or another braindisease like restless leg syndrome.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a compound according to formula (I), and one or morepharmaceutically acceptable carrier or excipient.

In one embodiment, the invention relates to a method for the treatmentof a neurodegenerative disorder, selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease or forthe treatment of a psychiatric disorder such as Attention Deficithyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome, which method comprises the administration of a therapeuticallyeffective amount of a compound according to formula (I) to a patient inneed thereof.

In one embodiment, the invention relates to the use of a compoundaccording to formula (I), for the manufacture of a medicament for thetreatment of a neurodegenerative disorder, selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease or for the treatment of a psychiatric disorder such as AttentionDeficit hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS), or another brain disease like restless legsyndrome.

Definitions PDE1 Enzymes:

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms unless otherwise specified.

PDE1 Inhibitors and PDE9 Inhibitors:

In the context of the present invention a compound is considered to be aPDE1 inhibitor if the amount required to reach the IC₅₀ level of any ofthe three PDE1 isoforms is 10 micro molar or less, preferably less than9 micro molar, such as 8 micro molar or less, such as 7 micro molar orless, such as 6 micro molar or less, such as 5 micro molar or less, suchas 4 micro molar or less, such as 3 micro molar or less, more preferably2 micro molar or less, such as 1 micro molar or less, in particular 500nM or less. In preferred embodiments the required amount of PDE1inhibitor required to reach the IC₅₀ level of PDE1B is 400 nM or less,such as 300 nM or less, 200 nM or less, 100 nM or less, or even 80 nM orless, such as 50 nM or less, for example 25 nM or less.

In a preferred embodiment the compounds of the present invention are atleast a ten-fold stronger as PDE1 inhibitors as PDE9 inhibitors, i.e.the amount of the compound required to reach the IC₅₀ level of one ormore of the three PDE1 isoforms is at least a ten-fold less than theamount of the same compound required to reach the IC₅₀ level of the PDE9enzyme.

Substituents:

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted ismono-, di-, or tri-substituted. It is understood that where nosubstituents are indicated for an “optionally substituted” moiety, thenthe position is held by a hydrogen atom.

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁-C₃ alkyl” is equivalent to “C₁ to C₃ alkyl”.

The terms “C₁-C₃ alkyl”, “C₁-C₄ alkyl”, “C₁-C₅ alkyl”, “C₁-C₆ alkyl”,“C₁-C₇ alkyl” and “C₁-C₈ alkyl” refer to a linear (i.e. unbranched) orbranched saturated hydrocarbon having from one up to eight carbon atoms,inclusive. Examples of such groups include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-butyl, n-hexyl, n-heptyl and n-octyl.

The term saturated monocyclic C₃-C₈ cycloalkyl refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “heteroaryl” refers to a 5 or 6 membered aromatic monocyclicring containing 1 to 5 carbon atoms and one or more heteroatoms selectedfrom oxygen, nitrogen and sulfur.

The term “dialkylamine” refers to an amino group substituted with twoC₁-C₃ alkyl groups.

The term “C₃-C₄ alkoxy” refers to a moiety of the formula —OR′, whereinR′ indicates C₁-C₃ alkyl as defined above. C₁-C₃ fluoroalkoxy refers toa C₁-C₃ alkoxy substituted with one or more fluorine.

The term “C₃-C₄ cycloalkoxy” refers to a moiety of the formula —OR′,wherein R′ is a saturated monocyclic C₃-C₄ cycloalkyl group. The term“C₄-C₅ methylcycloalkoxy” is refers to a methyl group substituted with aC₄-C₅ cycloalkoxy group.

Isomeric and Tautomeric Forms

Where compounds of the present invention contain one or more chiralcenters reference to any of the compounds will, unless otherwisespecified, cover the enantiomerically or diastereomerically purecompound as well as mixtures of the enantiomers or diastereomers in anyratio.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

Pharmaceutically Acceptable Salts:

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. When acompound of formula (I) contains a free base such salts are prepared ina conventional manner by treating a solution or suspension of a freebase of formula (I) with a molar equivalent of a pharmaceuticallyacceptable acid. Representative examples of suitable organic andinorganic acids are described below.

Pharmaceutically acceptable salts in the present context is intended toindicate non-toxic, i.e. physiologically acceptable salts. The termpharmaceutically acceptable salts includes salts formed with inorganicand/or organic acids such as hydrochloride acid, hydrobromide acid,phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citricacid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaricacid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaricacid, glutamic acid, pyroglutamic acid, salicylic acid, salicylic acid,saccharin and sulfonic acids, such as methanesulfonic acid,ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid. Someof the acids listed above are di- or tri-acids, i.e. acids containingtwo or three acidic hydrogens, such as phosphoric acid, sulphuric acid,fumaric acid and maleic acid.

Additional examples of useful acids and bases to form pharmaceuticallyacceptable salts can be found e.g. in Stahl and Wermuth (Eds) “Handbookof Pharmaceutical salts. Properties, selection, and use”, Wiley-VCH,2008.

Therapeutically Effective Amount:

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

Treatment and Treating:

In the present context, “treatment” or “treating” is intended toindicate the management and care of a patient for the purpose ofalleviating, arresting, partly arresting or delaying progress of theclinical manifestation of the disease, or curing the disease. Thepatient to be treated is preferably a mammal, in particular a humanbeing.

Administration Routes

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,buccal, sublingual, transdermal and parenteral (e.g. subcutaneous,intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical Formulations and Excipients

In the following, the term, “excipient” or “pharmaceutically acceptableexcipient” refers to pharmaceutical excipients including, but notlimited to, fillers, antiadherents, binders, coatings, colours,disintegrants, flavours, glidants, lubricants, preservatives, sorbents,sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a process for making apharmaceutical composition comprising a compound of formula (I). Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable excipients in accordance withconventional techniques such as those disclosed in Remington, TheScience and Practice of Pharmacy, 22^(th) edition (2012), Edited byAllen, Loyd V., Jr.

In an embodiment, the present invention relates to a pharmaceuticalcomposition comprising a compound of formula (I), such as one of thecompounds disclosed in the Experimental Section herein.

Pharmaceutical compositions for oral administration include solid oraldosage forms such as tablets, capsules, powders and granules; and liquidoral dosage forms such as solutions, emulsions, suspensions and syrupsas well as powders and granules to be dissolved or suspended in anappropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tabletsor hard or soft capsules), each containing a predetermined amount of theactive ingredient, and preferably one or more suitable excipients. Whereappropriate, the solid dosage forms may be prepared with coatings suchas enteric coatings or they may be formulated so as to provide modifiedrelease of the active ingredient such as delayed or extended releaseaccording to methods well known in the art. Where appropriate, the soliddosage form may be a dosage form disintegrating in the saliva, such asfor example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, butare not limited to, microcrystalline cellulose, corn starch, lactose,mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin,talcum, gelatin, pectin, magnesium stearate, stearic acid and loweralkyl ethers of cellulose. Similarly, the solid formulation may includeexcipients for delayed or extended release formulations known in theart, such as glyceryl monostearate or hypromellose.

If solid material is used for oral administration, the formulation mayfor example be prepared by mixing the active ingredient with solidexcipients and subsequently compressing the mixture in a conventionaltableting machine; or the formulation may for example be placed in ahard capsule e.g. in powder, pellet or mini tablet form. The amount ofsolid excipient will vary widely but will typically range from about 25mg to about 1 g per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs,syrups, oral drops or a liquid filled capsule. Liquid oral dosage formsmay also be presented as powders for a solution or suspension in anaqueous or non-aqueous liquid. Examples of excipients suitable forliquid oral formulation include, but are not limited to, ethanol,propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol,poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palmoil, and water. Liquid oral dosage forms may for example be prepared bydissolving or suspending the active ingredient in an aqueous ornon-aqueous liquid, or by incorporating the active ingredient into anoil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations,such as colourings, flavourings and preservatives etc.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous solutions, dispersions, suspensions oremulsions for injection or infusion, concentrates for injection orinfusion as well as sterile powders to be reconstituted in sterilesolutions or dispersions for injection or infusion prior to use.Examples of excipients suitable for parenteral formulation include, butare not limited to water, coconut oil, palm oil and solutions ofcyclodextrins. Aqueous formulations should be suitably buffered ifnecessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories,inhalants, creams, gels, dermal patches, implants and formulations forbuccal or sublingual administration.

It is requisite that the excipients used for any pharmaceuticalformulation comply with the intended route of administration and arecompatible with the active ingredients.

Doses:

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age, the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have identified compounds that are PDE1inhibitors, and as such are useful to treat neurodegenerative andpsychiatric disorders. Surprisingly, the compounds of the invention aresignificantly stronger as PDE1 inhibitors compared to being PDE9inhibitors,

The invention thus provides a compound of formula (I) or apharmaceutically acceptable salt thereof, as well as a pharmaceuticalcomposition containing such a compound, for use in the treatment ofanother brain disease which could be a neurodegenerative disorder or apsychiatric disorder. In a preferred embodiment, the neurodegenerativedisorder is selected from the group consisting of Alzheimer's Disease,Parkinson's Disease and Huntington's Disease. In another preferredembodiment, the psychiatric disorder is selected from the groupconsisting of Attention Deficit hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS). Other brain disorderscould be e.g. restless leg syndrome.

The present invention provides a method of treating a mammal, includinga human, suffering from a neurodegenerative disorder selected from thegroup consisting of Alzheimer's Disease, Parkinson's Disease andHuntington's Disease, which method comprises administering to thesubject a therapeutically effective amount of a compound of formula (I).

This invention further provides a method of treating a neurodegenerativedisorder in a mammal, including a human, which method comprisesadministering to said mammal an amount of a compound of formula (I)effective in inhibiting PDE1.

This invention also provides a method of treating a subject sufferingfrom a psychiatric disorder, which method comprises administering to thesubject a therapeutically effective amount of a compound of formula (I).Examples of psychiatric disorders that can be treated according to thepresent invention include Attention Deficit Hyperactivity Disorder(ADHD), depression, narcolepsy, cognitive impairment and cognitiveimpairment associated with schizophrenia (CIAS).

This invention also provides a method of treating a subject sufferingfrom a brain disorder such as restless leg syndrome.

Embodiments of the Invention

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth

In a first embodiment, E1, the present invention relates to compounds offormula (I).

-   E1. A compound of formula (I)

-   -   wherein    -   Y is N or CH;    -   R₁ is selected from the group consisting of linear or branched        C₂-C₈ alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,        tetrahydrofuranyl and tetrathydropyranyl; all of which can be        substituted one or more times with one or more substituents        selected from the group consisting of methyl, fluorine, hydroxy,        cyano or methoxy;    -   R₂ is selected from the group consisting of, linear or branched        C₁-C₈ alkyl, phenyl, benzo[1,3]dioxole and saturated monocyclic        C₃-C₈ cycloalkyl; or    -   R₂ is phenyl substituted one or more times with one or more        substituents selected from the group consisting of halogen,        C₁-C₃ alkyl and methoxy; or    -   R₂ is pyridyl substituted with a substituent selected from the        group consisting of halogen, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃        fluoroalkoxy, C₃-C₄ cycloalkoxy and C₄-C₅ methylcycloalkoxy; or    -   R₂ is selected from the group consisting of 5-membered        heteroaryls substituted with C₁-C₃ alkyl;    -   R₃ is selected from the group consisting of linear or branched        C₁-C₃ alkyl and saturated monocyclic C₃-C₈ cycloalkyl; which can        each be optionally substituted with a substituent selected from        halogen, C₁-C₃ alkoxy, phenyl, dialkylamine and oxetane; and        tautomers and pharmaceutically acceptable salts thereof.

-   E2. The compound of embodiment 1, wherein Y is N.

-   E3. The compound of embodiment 1, wherein Y is CH.

-   E4. The compound of any one of embodiments 1-3, wherein R₁ is a    linear or branched C₂-C₈ alkyl or a saturated monocyclic C₃-C₈    cycloalkyl such as cyclopropyl.

-   E5. The compound of embodiment 4, wherein said linear or branched    C₂-C₈ alkyl or saturated monocyclic C₃-C₈ cycloalkyl is substituted    one or more times with one or more substituents selected from the    group consisting of methyl, fluorine, hydroxy, cyano or methoxy.

-   E6. The compound of any one of embodiments 1-3, wherein R₁ is    selected from oxetanyl, tetrahydrofuranyl and tetrathydropyranyl.

-   E7. The compound of any one of embodiments 1-6, wherein R₂ is    phenyl.

-   E8. The compound of embodiment 7, wherein said phenyl is substituted    with one or more substituents selected from methyl, methoxy,    fluorine or chlorine.

-   E9. The compound of any one of embodiments 1-6, wherein R₂ is    pyridyl substituted with a substituent selected from methyl,    methoxy, fluorine or chlorine.

-   E10. The compound of any one of embodiments 1-6, wherein R₂ is a    saturated monocyclic C₃-C₈ cycloalkyl such as cyclohexyl.

-   E11. The compound of any one of embodiments 1-10, wherein R₃ is C₁₋₃    alkyl such as methyl.

-   E12. The compound of any one of embodiments 1-10, wherein R₃ is    methyl substituted with a phenyl.

-   E13. The compound of any one of embodiments 1-10, wherein R₃ is    methyl substituted with a methoxy or oxetane

-   E14. The compound of embodiment 1, wherein    -   Y is N or CH;    -   R₁ is selected from the group consisting of linear or branched        C₂-C₈ alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,        tetrahydrofuranyl, and tetrathydropyranyl; all of which can be        substituted one or more times with one or more substituents        selected from the group consisting of methyl, fluorine, hydroxy,        cyano or methoxy;    -   R₂ is selected from the group consisting of phenyl,        benzo[1,3]dioxole, and saturated monocyclic C₃-C₈ cycloalkyl; or    -   R₂ is phenyl substituted one or more times with one or more        substituents selected from the group consisting of halogen,        C₁-C₃ alkyl and C₁-C₃ alkoxy; or    -   R₂ is pyridine substituted with a substituent selected from the        group consisting of halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy, C₁-C₃        fluoroalkoxy, C₃-C₄ cycloalkoxy and C₄-C₅ methylcycloalkoxy;    -   R₃ is C₁-C₃ alkyl such as methyl; which can each be optionally        substituted with a substituent selected from halogen, C₁-C₃        alkoxy, phenyl and oxetane.

-   E15. The compound of embodiment 6, wherein said oxetanyl,    tetrahydrofuranyl or tetrathydropyranyl is optionally substituted    with methyl.

-   E16. The compound of embodiment 1, wherein the compound is selected    from the group consisting of:

-   6-benzyl-5-(cyclohexylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;

-   5-(cyclohexylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one;

-   5-(cyclohexylmethyl)-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one;

-   6-ethyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   6-(methoxymethyl)-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   6-isopropyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-(oxetan-3-ylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;

-   5-[(3-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(2-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-benzyl-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(3-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   6-methyl-5-(p-tolylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-(1,    3-benzodioxol-5-ylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(6-methoxy-3-pyridyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one;

-   5-(4-methoxybenzyl)-6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one;

-   1-isopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridin-4-one;

-   1-cyclopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one:

-   1-ethyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydropyran-3-yl-pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(2S,3R)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(2R,3R)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one;

-   5-[(4-methoxyphenyl)methyl]-6-methyl-1-(oxetan-3-yl)    pyrazolo[4,3-c]pyridin-4-one;

-   5-(4-methoxybenzyl)-6-methyl-1-(4-methyltetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one;    -   and pharmaceutically acceptable salts of any of these compounds.

-   E17. A compound of any one of embodiments 1-16, wherein said    compound has a PDE1A, PDE1B or PDE1C IC₅₀ value, determined as    described in the section “PDE1 inhibition assay”, of 10 micro molar    or less, such as 5 micro molar or less, such as 4 micro molar or    less, such as 3 micro molar or less, such as 2 micro molar or less,    such as 1 micro molar or less, such as 500 nM or less, such as 400    nM or less, such as 300 nM or less, such as 200 nM or less, such as    100 nM or less.

-   E18. A compound of any one of embodiments 1-17 for use in therapy.

-   E19. A compound according to any of embodiments 1-17, for use as a    medicament.

-   E20. A pharmaceutical composition comprising a therapeutically    effective amount of a compound of any one of embodiments 1-17 and    one or more pharmaceutically acceptable carriers, diluents and    excipients.

-   E21. A compound according to any of embodiments 1-17 for use in the    treatment of a neurodegenerative disorder, selected from the group    consisting of Alzheimer's Disease, Parkinson's Disease and    Huntington's Disease or for the treatment of a psychiatric disorder    such as Attention Deficit Hyperactivity Disorder (ADHD), depression,    anxiety, narcolepsy, cognitive impairment and cognitive impairment    associated with schizophrenia (CIAS), or another brain disease like    restless leg syndrome.

-   E22. A method for the treatment of a neurodegenerative disorder,    selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome, which    method comprises the administration of a therapeutically effective    amount of a compound according to any of embodiments 1-17 to a    patient in need thereof.

-   E23. Use of a compound according to any of embodiments 1-17, for the    manufacture of a medicament for the treatment of a neurodegenerative    disorder, selected from the group consisting of Alzheimer's Disease,    Parkinson's Disease and Huntington's Disease or for the treatment of    a psychiatric disorder such as Attention Deficit Hyperactivity    Disorder (ADHD), depression, anxiety, narcolepsy, cognitive    impairment and cognitive impairment associated with schizophrenia    (CIAS), or another brain disease like restless leg syndrome.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

COMPOUNDS OF THE INVENTION

TABLE 1 Compounds of the invention PDE1A, PDE1B, PDE1C, % inhibitionIC₅₀ IC₅₀ IC₅₀ of PDE9 at Example Compound (nM) (nM) (nM) 10 microM 16-benzyl-5-(cyclohexylmethyl)-1- 349 320 120 51tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 25-(4-methoxybenzyl)-6-methyl-1- 132 62 74 10(tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-d]pyrimidin-4(5H)-one 35-(cyclohexylmethyl)-6-methyl-1- 172 103 29 29tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 45-[(4-methoxyphenyl)methyl]-6- 108 68 72 13methyl-1-propyl-pyrazolo[3,4- d]pyrimidin-4-one 55-(cyclohexylmethyl)-6-methyl-1- 111 31 36 −16propyl-pyrazolo[3,4-d]pyrimidin-4- one 66-ethyl-5-[(4-methoxyphenyl)methyl]- 107 80 140 21-tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 76-(methoxymethyl)-5-[(4- 325 181 345 −12 methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 86-isopropyl-5-[(4- 751 211 1324 7 methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 95-[(4-methoxyphenyl)methyl]-6- nd 58 165 12 (oxetan-3-ylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4- d]pyrimidin-4-one 105-[(3-fluorophenyl)methyl]-6-methyl- 1070 361 149 31-tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 115-[(2-fluorophenyl)methyl]-6-methyl- 589 250 61 121-tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 125-[(4-chlorophenyl)methyl]-6-methyl- 127 65 419 161-tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 135-benzyl-6-methyl-1- 1264 309 135 −18 tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one 14 5-[(3-chlorophenyl)methyl]-6-methyl- 1303 413 95 −151-tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 155-[(4-fluorophenyl)methyl]-6-methyl- 1240 258 204 −131-tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 166-methyl-5-(p-tolylmethyl)-1- 400 71 496 −1tetrahydropyran-4-yl-pyrazolo[4,3- c]pyridin-4-one 175-(1,3-benzodioxol-5-ylmethyl)-6- 429 154 662 −2methyl-1-tetrahydropyran-4-yl- pyrazolo[4,3-c]pyridin-4-one 185-[(6-methoxy-3-pyridyl)methyl]-6- 738 370 1167 9methyl-1-tetrahydropyran-4-yl- pyrazolo[4,3-c]pyridin-4-one 195-(4-methoxybenzyl)-6-methyl-1- 184 88 171 19(tetrahydro-2H-pyran-4-yl)-1,5- dihydro-4H-pyrazolo[4,3-c]pyridin-4- one20 5-(4-methoxybenzyl)-6-methyl-1- 290 82 233 19propyl-1,5-dihydro-4H-pyrazolo[4,3- c]pyridin-4-one 211-isopropyl-5-[(4- 49 37 134 −14 methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one 22 5-[(4-methoxyphenyl)methyl]-6- 1691 5691205 8 methyl-1-tetrahydrofuran-3-yl- pyrazolo[4,3-c]pyridin-4-one 231-cyclopropyl-5-[(4- 543 255 975 −6 methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one 24 1-ethyl-5-[(4-methoxyphenyl)methyl]-1115 329 1326 19 6-methyl-pyrazolo[4,3-c]pyridin-4- one 255-[(4-methoxyphenyl)methyl]-6- 825 113 644 8methyl-1-tetrahydropyran-3-yl- pyrazolo[4,3-c]pyridin-4-one 265-[(4-methoxyphenyl)methyl]-6- 206 83 345 8 methyl-1-[(2S,3R)-2-methyltetrahydrofuran-3- yl]pyrazolo[4,3-c]pyridin-4-one 275-[(4-methoxyphenyl)methyl]-6- 1303 179 686 13 methyl-1-[(2R,3R)-2-methyltetrahydrofuran-3- yl]pyrazolo[4,3-c]pyridin-4-one 285-[(4-methoxyphenyl)methyl]-6- 63% 704 2185 14methyl-1-(oxetan-3-yl)pyrazolo[4,3- inhibition c]pyridin-4-one @10 μM 295-(4-methoxybenzyl)-6-methyl-1-(4- 119 87 174 26methyltetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4- one nd means “not determined”

Table 1 lists the IC₅₀ value for inhibition of PDE1 by the compounds ofthe invention. The IC₅₀ value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration.

For comparative purpose, the table also lists % inhibition of PDE9 at 10μM, which refers to the % inhibition of the PDE9 enzyme obtained at aconcentration of 10 micro molar of the compound.

PDE1 and PDE9 assays are described in the Experimental Section.

EXPERIMENTAL SECTION Preparation of the Compounds of theInvention—General Methods

The compounds of formula (I) may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethod described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XIII” (published withWiley-Interscience, ISSN: 1934-4783). Preferred methods include, but arenot limited to, those described below.

The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Method 1:

where R₁ and R₃ are as described for formula I and R₄ is an alkyl groupsuch as methyl or ethyl.

Compounds of general formula II (Scheme 1) can be prepared as describedin the literature (J. Med. Chem. 2009, 52, 7949). Compounds of generalformula IVa can be prepared from compounds of general formulae II andIII as described in the literature (J. Med. Chem. 2009, 52, 7949).

Method 2:

where R₂ and R₃ are as described for formula I.

Compounds of general formula VII (Scheme 2) can be prepared by heating amixture of compounds of general formulae V and VI in a solvent such aswater. Compounds of general formula VIII can be prepared by treatingcompounds of general formula VII with phosphoryl chloride and dimethylformamide.

Method 3:

where R₁ and R₃ are as described for formula I.

Compounds of general formula IV (Scheme 3) can be prepared by treatmentof compounds of general formula IX with an acid such as trifluoroaceticacid.

Method 4:

where R₁, R₂ and R₃ are as described for formula I and X is a leavinggroup such as but not limited to chloride, bromide, iodide or mesylate.

Compounds of general formula I (Scheme 4) can be prepared by treatmentof compounds of general formula X with compounds of general formula XIin the presence of a base such as but not limited to potassium carbonateor cesium carbonate.

Method 5:

where R₁, R₂ and R₃ are as described for formula I and Y is CH.

Compounds of general formula I (Scheme 5) can be prepared by treatmentof compounds of general formula VIII with hydrazines of general formulaXII.

Method 6:

where R₁, R₂ and R₃ are as described for formula I, X is a leaving groupsuch as but not limited to chloride, bromide, iodide or mesylate and Yis CH.

Compounds of general formula I (Scheme 6) can be prepared by treatmentof compounds of general formula VIII with hydrazine followed byalkylation with compounds of general formula XIV.

General Methods LC-MS Methods

Method A:

An Agilent 1200 LCMS system with ELS detector was used. Column: AgilentTC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method B:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1*50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=95:5 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method C:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method D:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/minute.

Method E:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/water/formic acid (94.9:5:0.1);Method: Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutesand with a flow rate of 1.2 mL/minute.

INTERMEDIATES Intermediate:5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile

To a mixture of (tetrahydro-2H-pyran-4-yl)hydrazine dihydro chloride(5.0 g, 26 mmol) and Et₃N (5.62 g, 55.5 mmol) in EtOH (100 mL) was added2-(ethoxymethylene)malononitrile (3.23 g, 26.4 mmol). The mixture wasstirred at 60° C. for 1 hour. Solvent was removed under vacuum. Theresidue was washed with water (40 mL) then DCM (40 mL). The filter cakewas dried under vacuum to give5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile (2.3 g,45% yield).

The following intermediate was prepared in a similar manner:

-   5-amino-1-cyclopropyl-1H-pyrazole-4-carbonitrile and    5-amino-1-propyl-1H-pyrazole-4-carbonitrile

Intermediate:5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide

To a mixture of5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carbonitrile (2.3 g,12 mmol) in EtOH (40 mL) were added H₂O₂ (10 mL) and NH₃.H₂O in water(10 mL). The mixture was stirred at 20° C. for 12 hours. The mixture wasquenched with 2N Na₂SO₃ (40 mL) and evaporated under vacuum. The residuewas washed with water (20 mL×2). The filter cake was dried under vacuumto give 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide(1.3 g, 51% yield).

The following intermediates were prepared in a similar manner:

-   5-amino-1-cyclopropyl-1H-pyrazole-4-carboxamide; and-   5-amino-1-propyl-1H-pyrazole-4-carboxamide

Intermediate:6-benzyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (100 mg,0.47 mmol) and ethyl 2-phenylacetate (234 mg, 1.43 mmol) in EtOH (4 mL)was added NaOEt (97 mg, 1.43 mmol). The mixture was stirred at 140° C.for 1 hour under microwave conditions. Solvent was removed under vacuum.The residue was purified by prep TLC (DCM:MeOH=10:1) to give6-benzyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(120 mg, yield: 77%).

The following intermediate was prepared in a similar manner:

-   6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Intermediate:6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide (1.0 g,4.76 mmol) and triethyl orthoformate (7.72 g, 47.6 mmol) in DMSO (20 mL)was added Cs₂CO₃ (3.1 g 9.5 mmol). The mixture was stirred at 130° C.for 36 hours. The mixture was diluted with water (100 mL) and extractedwith DCM (30 mL×3). The organic layer was washed with water (30 mL×2)and dried over Na₂SO₄. The organic layer was evaporated under vacuum.The mixture was purified by silica gel chromatography (DCM: MeOH from20:1 to 5:1) to give6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(560 mg, 50% yield).

The following intermediates were prepared in a similar manner:

-   6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    prepared from 5-amino-1-propyl-1H-pyrazole-4-carboxamide and    triethyl orthoformate;-   6-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    prepared from    5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide    methyl propionate;-   6-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    prepared from    5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide    methyl 2-methoxyacetate;-   6-isopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    prepared from    5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide    methyl isobutyrate; and-   6-(oxetan-3-ylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,    prepared from    5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide    methyl 2-(oxetan-3-yl)acetate.

Intermediate: 4-hydroxy-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one

To a solution of 4-hydroxy-6-methyl-2H-pyran-2-one (12 g, 95 mmol) inH₂O (200 mL) was added (4-methoxyphenyl)methanamine (13.05 g, 95.16mmol). The mixture was stirred at 100° C. for 16 hours. A solid wasobtained. The mixture was filtered. The filter cake was dried undervacuum to give 4-hydroxy-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one(22.0 g, 63.7 mmol, 67% yield) which was used to the next step directly.¹H NMR (DMSO-d₆ 400 MHz): δ 10.49 (br. s, 1H), 7.02 (d, J=8.4 Hz 2H),6.85 (d, J=8.4 Hz, 2H), 5.74 (s, 1H), 5.55 (s, 1H), 5.07 (s, 2H), 3.68(s, 3H), 2.14 (s, 3H).

Intermediate:4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde

To a solution of 4-hydroxy-1-(4-methoxybenzyl)-6-methylpyridin-2(1H)-one(10 g, 29 mmol) in DMF (100 mL) was added POCl₃ (11.1 g, 72.4 mmol)dropwise. The resulting mixture was stirred at 60° C. for 3 hours. Themixture was poured into ice water (700 g) and extracted with ethylacetate (500 ml×2). The organic layer was washed with water (500 mL×2)and brine (500 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography on silica gel (40% ethyl acetate inpetroleum ether) to give4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde(4.0 g, 8.2 mmol, 28% yield).

Intermediate:6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

A solution of5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(1.30 g, 3.68 mmol) in TFA (40 mL) was stirred at 80-90° C. for 72hours. The mixture was concentrated. The crude was purified by columnchromatography on silica gel (using a gradient of petroleum ether andethyl acetate) to give6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(500 mg, 1.8 mmol, 48% yield).

Intermediate: tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate

A solution of tert-butyl hydrazinecarboxylate (3.0 g, 23 mmol) inacetone (20 mL) was stirred at 20° C. for 16 hours. The mixture wasconcentrated to give tert-butyl2-(propan-2-ylidene)hydrazine-1-carboxylate (3.9 g, 23 mmol, 99% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.33 (br. s, 1H), 2.02 (s, 3H), 1.80 (s, 3H),1.50 (s, 9H).

Intermediate: tert-butyl 2-isopropylhydrazine-1-carboxylate

To a solution of tert-butyl 2-(propan-2-ylidene)hydrazine-1-carboxylate(3.90 g, 22.7 mmol) in THF (22 mL) and MeOH (22 mL) was added NaBH(OAc)₃(4.80 g, 22.7 mmol) portionwise. The resulted mixture was refluxed underN₂ balloon for 2 h and then cooled to 25° C. for 16 hours. The mixturewas concentrated. The crude was purified by column chromatograph onsilica gel (petroleum ether:ethyl acetate=4:1). The product wasrecrystallized by ethyl acetate and petroleum ether to give tert-butyl2-isopropylhydrazine-1-carboxylate (400 mg, 2.30 mmol, 10% yield).

¹H NMR (CDCl₃ 400 MHz): δ 6.67 (br. s, 1H), 5.99-5.98 (m, 1H), 3.54-3.48(m, 1H), 1.51 (s, 9H), 1.26 (d, J=6.8 Hz, 6H).

Intermediate: isopropylhydrazine hydrochloride

To a solution of tert-butyl 2-isopropylhydrazine-1-carboxylate (400 mg,2.30 mmol) in ethyl acetate (5 mL) was added HCl/dioxane (5 mL). Theresulted mixture was stirred at 20° C. for 16 hours. The mixture wasconcentrated to give isopropylhydrazine hydrochloride (300 mg) which wasused to the next step directly.

Intermediate: tert-butyl2-(dihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate

A solution of dihydrofuran-3(2H)-one (5.0 g, 58 mmol) and tert-butylhydrazinecarboxylate (7.68 g, 58.08 mmol) in MeOH (50 mL) was stirred at15° C. for 2 hours. The mixture was concentrated to remove MeOH andafford tert-butyl 2-(dihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate(11 g, 55 mmol, 95% yield).

¹H NMR (MeOD 400 MHz): δ4.19 (s, 2H), 4.03 (t, J=6.8 Hz, 2H), 2.53 (t,J=7.2 Hz, 2H), 1.50 (s, 9H).

Intermediate: tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1-carboxylate

A solution of tert-butyl2-(dihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate (11 g, 55 mmol) inAcOH (30 mL) and H₂O (60 mL) was stirred at 15° C. for 0.5 hours. ThenNaBH₃CN (3.80 g, 60.4 mmol) was added to the solution in portions. Theresulted mixture was stirred at 15° C. for 2 hours. The mixture wasneutralized with 2M NaOH(500 mL) and extracted with DCM(100 mL×3), theorganic layer was washed with brine(300 mL×3), dried with anhydrousNa₂SO₄, filtrated and concentrated. The crude was purified by columnchromatography on silica gel (ethyl acetate) to afford the tert-butyl2-(tetrahydrofuran-3-yl)hydrazine-1-carboxylate (11 g, crude).

Intermediate: (tetrahydrofuran-3-yl)hydrazine hydrochloride

To a solution of tert-butyl2-(tetrahydrofuran-3-yl)hydrazine-1-carboxylate (2.0 g, 9.9 mmol) inMeOH (50 mL) was added HCl/dioxane (4 M, 9.1 mL) dropwise. The solutionwas stirred at 0° C. for 2 hours. The mixture was filtrated to removethe solvent and afford the (tetrahydrofuran-3-yl)hydrazine hydrochloride(1 g).

Intermediate: di-tert-butyl 1-cyclopropylhydrazine-1,2-dicarboxylate

To a solution of cyclopropylmagnesium bromide (0.5 M, 11.02 mL) in THF(10 mL) was added di-tert-butyl azadicarboxylate (1.27 g, 5.51 mmol) at−78° C. under argon. The mixture was stirred at −78° C. for 0.5 hour.The reaction mixture was quenched by addition NH₄Cl (sat.aq. 10 mL) at0° C., and then diluted with H₂O (60 mL) and extracted with ethylacetate (100 mL×2). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flash silica gelchromatography (using a gradient of ethyl acetate and petroleum ether)to give di-tert-butyl 1-cyclopropylhydrazine-1,2-dicarboxylate (1.20 g,4.41 mmol, 80% yield. ¹H NMR (MeOD 400 MHz): δ 2.84-2.92 (m, 1H), 1.46(s, 18H), 0.67 (s, 4H).

Intermediate: cyclopropylhydrazine hydrochloride

Di-tert-butyl 1-cyclopropylhydrazine-1,2-dicarboxylate (1.20 g, 4.41mmol) was dissolved in HCl/dioxane (10 mL). The mixture was stirred at15° C. for 12 hours. The reaction mixture was concentrated under reducedpressure to give cyclopropylhydrazine hydrochloride (0.45 g, 4.14 mmol,94% yield). ¹H NMR (MeOD 400 MHz): δ 2.58-2.63 (m, 1H), 0.60-0.70 (m,4H).

Intermediate:5-(4-methoxybenzyl)-6-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

A mixture of NH₂NH₂.H₂O (35 mg, 0.69 mmol),4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde(200 mg, 0.69 mmol) and triethylamine (208 mg, 2.06 mmol) in EtOH (3 mL)was stirred at 130° C. under microwave irradiation for 1 hour. Themixture was concentrated and the crude was purified by preparative TLC(ethyl acetate) to give5-(4-methoxybenzyl)-6-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(130 mg, 0.472 mmol, 69% yield).

Intermediate: benzyl2-(2-methyldihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate

A solution of 2-methyldihydrofuran-3(2H)-one (5.0 g, 50 mmol) and benzylN-aminocarbamate (8.3 g, 50 mmol) in dry MeOH (150 mL) was stirred at15° C. for 16 hours.

The mixture was concentrated to give benzyl2-(2-methyldihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate (12 g, 97%yield)

Intermediates: benzyl2-(cis-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate and benzyl2-(trans-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate

To a solution of benzyl2-(2-methyldihydrofuran-3(2H)-ylidene)hydrazine-1-carboxylate (12 g, 48mmol) in H₂O (96 mL) was added AcOH (40 mL). The mixture was stirred at15° C. for 1 hour. Then NaBH₃CN (3.34 g, 53.2 mmol) was added in smallportions. The mixture was stirred at 15° C. for 2 hours. The mixture wasadjusted to pH=8 by 5 N NaOH (aq). The mixture was extracted with ethylacetate (200 mL×2). The combined organic layers were washed with H₂O(200 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated.The crude product was purified by flash chromatography on silica gel(using a gradient of ethyl acetate and petroleum ether) to give amixture of benzyl2-(cis-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate and benzyl2-(trans-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate (6.0 g,50% yield). 2 g of the mixture was purified by SFC twice to give

benzyl 2-(trans-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate(700 mg, 32.5% yield) (Rt=5.671 min (1^(st) run), 5.754 min (2^(nd)run))¹H NMR (CDCl₃ 400 MHz): δ 7.35 (s, 5H), 6.23 (s, 1H), 5.13 (s, 2H),3.99-3.97 (m, 2H), 3.85-3.84 (m, 1H), 3.74-3.68 (m, 1H), 3.59 (bs, 1H),2.10-2.08 (m, 1H), 1.88-1.87 (m, 1H), 1.28 (d, J=6.0 Hz, 3H).

and benzyl 2-(cis-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate(450 mg, 20.7% yield) (Rt=8.354 min). ¹H NMR (CDCl₃ 400 MHz): δ 7.35 (s,5H), 6.22 (s, 1H), 5.13 (s, 2H), 3.99-3.97 (m, 2H), 3.87-3.86 (m, 1H),3.74-3.68 (m, 1H), 3.59 (bs, 1H), 2.10-2.07 (m, 1H), 1.88-1.87 (m, 1H),1.28 (d, J=6.0 Hz, 3H).

SFC condition 1: Instrument: SFC-80-(8); Column: AD 250 mm×30 mm, 5 μm;Mobile phase: A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O), A:B=70:30 at60 mL/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp:60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.; Wavelength: 220nm

SFC condition 2: Instrument: MG-II; Column: AY250 mm×30 mm, 10 μm;Mobile phase: A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O), A:B=75:25 at60 ml/min; Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp:60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25° C.; Wavelength: 220nm

Intermediate: cis-(2-methyltetrahydrofuran-3-yl)hydrazine hydrochloride

To a solution of benzyl2-(cis-2-methyltetrahydrofuran-3-yl)hydrazine-1-carboxylate (800 mg,3.20 mmol) in MeOH (20 mL) was added 1 M HCl (1 M, 9.6 mL) and Pd/C (500mg) (wet, 10% Pd with 50% of water) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred at 25° C. under H₂ (40 psi) for 16 hours. The mixture wasfiltered through celite and the filtrate was concentrated to givecis-(2-methyltetrahydrofuran-3-yl)hydrazine hydrochloride (450 mg, 92%yield)¹H NMR (DMSO d₆ 400 MHz): δ 8.55 (bs, 1H), 8.18 (bs, 1H),7.43-7.18 (m, 1H), 3.88-3.79 (m, 2H), 3.57-3.51 (m, 2H), 2.06-2.02 (m,2H), 1.10 (d, J=6.4 Hz, 3H).

Intermediate: tert-butyl2-(dihydro-2H-pyran-3(4H)-ylidene)hydrazine-1-carboxylate

A solution of tert-butyl hydrazinecarboxylate (6.6 g, 50 mmol) anddihydro-2H-pyran-3(4H)-one (5 g, 50 mmol) in MeOH (50 mL) was stirred at15° C. for 2 hours. The mixture was concentrated to remove MeOH and thecrude was purified by column chromatography on silica gel (petroleumether:ethyl acetate=1:1) to afford tert-butyl2-(dihydro-2H-pyran-3(4H)-ylidene)hydrazine-1-carboxylate (10 g, 47mmol, 93% yield).

Intermediate: tert-butyl2-(tetrahydro-2H-pyran-3-yl)hydrazine-1-carboxylate

A mixture of tert-butyl2-(dihydro-2H-pyran-3(4H)-ylidene)hydrazine-1-carboxylate (10 g, 47mmol) in AcOH (50 mL) and H₂O (100 mL) was stirred at 15° C. for 0.5hours. Then NaBH₃CN (3.23 g, 51 mmol) was added to the solution. Theresulted mixture was stirred at 15° C. for 2 hours. The mixture wasbasified with 2M NaOH (aq) (200 mL) and extracted with DCM (100 mL×3),the organic layer was washed with brine (200 mL), dried with anhydrousNa₂SO₄, filtrated and concentrated to afford the crude product. Thecrude was purified by column chromatography on silica gel (ethylacetate) to afford tert-butyl2-(tetrahydro-2H-pyran-3-yl)hydrazine-1-carboxylate (9 g).

Intermediate: (tetrahydro-2H-pyran-3-yl)hydrazine hydrochloride

To a solution of tert-butyl2-(tetrahydro-2H-pyran-3-yl)hydrazine-1-carboxylate (550 mg, 2.54 mmol)in MeOH (10 mL) and ethyl acetate (10 mL) was added HCl/MeOH (20 mL).The resulted mixture was stirred at 10° C. for 3 hours. The mixture wasconcentrated to give (tetrahydro-2H-pyran-3-yl)hydrazine hydrochloride(500 mg) which was used to the next step directly.

Intermediate: 4-isocyanato-4-methyltetrahydro-2H-pyran

To a solution of compound 4-methyltetrahydro-2H-pyran-4-carboxylic acid(4.00 g, 27.8 mmol) and triethylamine (4.21 g, 41.6 mmol, 5.77 mL intoluene (100 mL) was added DPPA (8.40 g, 30.53 mmol, 6.61 mL). Themixture was stirred at 85° C. for 2 h. The reaction mixture was treatedwith 1M NaOH(aq) (50 mL), extracted with EtOAc (100 mL*2). The organiclayer was washed with brine (20 mL) and dried over Na₂SO₄ andconcentrated in vacuo to give 4-isocyanato-4-methyltetrahydro-2H-pyran(2 g).

Intermediate: 4-methyltetrahydro-2H-pyran-4-amine

To a solution of compound 4-isocyanato-4-methyltetrahydro-2H-pyran (3.00g, 21 mmol, 1 eq) in THF (20 mL) was added 5M HCl (aq) (20 mL). Themixture was stirred at 10-15° C. for 16 hours. The mixture wasconcentrated in vacuo, and dissolved in dichloromethane (30 mL) andfiltered. The filter cake was dried to give4-methyltetrahydro-2H-pyran-4-amine hydrochloride. To a suspension of4-methyltetrahydro-2H-pyran-4-amine hydrochloride (200 mg, 1.32 mmol, 1eq) in dichloromethane (5 mL) was added ion exchange resin (100 mg). Themixture was stirred at 15-20° C. for 5 min. The mixture was filtered andthe filtrate was used for next step directly. A solution of4-methyltetrahydro-2H-pyran-4-amine in dichloromethane (5 mL) wasobtained.

Intermediate: tert-butyl2-(4-methyltetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate

To a solution of tert-butyl3-(4-cyanophenyl)-1,2-oxaziridine-2-carboxylate (Journal of OrganicChemistry, 58(18), 4791, 1993) (1 eq) in dichloromethane (5 mL) wasadded 4-methyltetrahydro-2H-pyran-4-amine (200 mg, 0.81 mmol). Themixture was stirred at 15-20° C. for 16 hours and at reflux (50° C.) for4 hours. The reaction mixture was diluted with dichloromethane (20 mL),washed with water (20 mL) and brine (10 mL), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:1) to give tert-butyl2-(4-methyltetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate (100 mg)

Intermediate: (4-methyltetrahydro-2H-pyran-4-yl)hydrazine hydrochloride

A solution of tert-butyl2-(4-methyltetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate (100 mg,0.30 mmol, 1 eq) in HCl in ethyl acetate (5 mL) was stirred at 15-20° C.for 1 hour. The mixture was filtered and the filter cake was washed withethyl acetate (2×10 mL) and dried to give(4-methyltetrahydro-2H-pyran-4-yl)hydrazine hydrochloride (30 mg)

COMPOUNDS OF THE INVENTION Example 1:6-benzyl-5-(cyclohexylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

To a solution of6-benzyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(200 mg, 0.64 mmol) and (bromomethyl)cyclohexane (137 mg, 0.77 mmol) inDMF (2 mL) was added K₂CO₃ (178 mg, 1.29 mmol). The mixture was stirredat 100° C. for 8 hours. The mixture was diluted with ethyl acetate (10mL) and washed with water (3 mL×2). The organic layer was dried overNa₂SO₄ and evaporated. The residue was purified by preparative TLC (DCM:ethyl acetate) to give6-benzyl-5-(cyclohexylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one(20 mg, yield: 7%).

¹H NMR (CDCl3, 400 MHz): δ 8.05 (m, 2H), 7.53-7.28 (m, 3H), 7.18 (d,J=6.8 Hz, 2H), 4.87-4.79 (m, 1H), 4.24 (s, 1H), 4.16-4.12 (m, 2H),3.91-3.83 (bs, 2H), 3.60 (t, J=7.6 Hz, 2H), 2.45-2.36 (m, 2H), 1.97-1.94(m, 2H), 1.74-1.63 (m, 7H), 1.17-1.09 (m, 4H). LC-MS: t_(R)=3.24 min(Method A), m/z=407.2 (MH⁺).

The following compounds were prepared in a similar manner:

Example 2:5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand 1-(chloromethyl)-4-methoxybenzene.

¹HNMR (CDCl₃, 400 MHz): δ 8.10 (s, 1H), 7.14 (d, J=8.4, 2H), 6.86 (d,J=8.4, 2H), 5.30 (s, 2H), 4.86-4.79 (m, 1H), 4.17-4.13 (m, 2H), 3.79 (s,3H), 3.63-3.58 (m, 2H), 2.55 (s, 3H), 2.45-2.36 (m, 2H), 1.94-1.90 (m,2H). LC-MS (m/z) 355.1 (MH⁺); t_(R)=0.61 (Method D)

Example 3:5-(cyclohexylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand (bromomethyl)cyclohexane.

¹HNMR (CDCl3, 400 MHz): δ 8.03 (s, 1H), 4.85-4.77 (m, 1H), 4.16-4.13 (m,2H), 3.93 (bs, 2H), 3.64-3.58 (m, 2H), 2.63 (s, 3H), 2.44-2.35 (m, 2H),1.93-1.65 (m, 8H), 1.20-1.09 (m, 5H). LC-MS (m/z) 331.2 (MH⁺);t_(R)=2.63 (Method C)

Example 4:5-[(4-methoxyphenyl)methyl]-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one and1-(chloromethyl)-4-methoxybenzene.

¹HNMR (CDCl₃, 400 MHz): δ 8.08 (s, 1H), 7.14 (d, J=8.4 Hz 2H), 6.86 (d,J=8.4 Hz 2H), 5.30 (bs, 2H), 4.27 (t, J=7.2 Hz, 2H), 3.79 (s, 3H), 2.55(s, 3H), 1.97-1.92 (m, 2H), 0.94 (t, J=7.2 Hz, 3H). LC-MS (m/z) 313.1(MH⁺); t_(R)=2.54 (Method C)

Example 5:5-(cyclohexylmethyl)-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one and(bromomethyl)cyclohexane.

¹HNMR (CDCl₃, 400 MHz): δ 8.02 (s, 1H), 4.25 (t, J=7.2 Hz, 2H), 3.93(bs, 2H), 2.63 (s, 3H), 1.96-1.91 (m, 2H), 1.74-1.65 (m, 6H), 1.20-1.09(m, 5H), 0.94 (t, J=7.2 Hz, 3H). LC-MS (m/z) 289.2 (MH⁺); t_(R)=2.84(Method C)

Example 6:6-ethyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand 1-(chloromethyl)-4-methoxybenzene.

¹H NMR (CDCl₃400 MHz): δ 8.07 (s, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.83 (d,J=8.4 Hz, 2H), 5.30 (bs, 2H), 4.84-4.78 (m, 1H), 4.15-4.13 (m, 2H), 3.76(s, 3H), 3.60 (t, J=12.0 Hz, 2H), 2.77 (q, J=7.6 Hz, 2H), 2.46-2.36 (m,2H), 1.95-1.92 (m, 2H), 1.28 (t, J=6.8 Hz, 3H). LC-MS (m/z) 369.2 (MH⁺);t_(R)=2.34 (Method B).

Example 7:6-(methoxymethyl)-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-(methoxymethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand 1-(chloromethyl)-4-methoxybenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.11 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.84 (d,J=7.6 Hz, 2H), 5.46 (s, 2H), 4.88-4.83 (m, 1H), 4.43 (s, 2H), 4.15-4.12(m, 2H), 3.77 (s, 3H), 3.60 (t, J=12.0 Hz, 2H), 3.46 (s, 3H), 2.45-2.34(m, 2H), 1.92 (d, J=12.0 Hz, 2H). LC-MS (m/z) 385.2 (MH⁺); t_(R)=2.42(Method C).

Example 8:6-isopropyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-isopropyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand 1-(chloromethyl)-4-methoxybenzene.

¹H NMR (CDCl₁ 400 MHz): δ 8.07 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.85 (d,J=8.4 Hz, 2H), 5.36 (bs, 2H), 4.84-4.78 (m, 1H), 4.17-4.13 (m, 2H), 3.78(s, 3H), 3.64-3.58 (m, 2H), 3.18-3.13 (m, 1H), 2.47-2.38 (m, 2H),1.98-1.94 (m, 2H), 1.24-1.22 (d, J=6.4 Hz, 6H). LC-MS (m/z) 383.2 (MH⁺);t_(R)=2.76 (Method C).

Example 9:5-[(4-methoxyphenyl)methyl]-6-(oxetan-3-ylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one

Prepared from6-(oxetan-3-ylmethyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-oneand 1-(chloromethyl)-4-methoxybenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.07 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.85 (d,J=8.4 Hz, 2H), 5.36 (bs, 2H), 4.84-4.78 (m, 1H), 4.17-4.13 (m, 2H), 3.78(s, 3H), 3.64-3.58 (m, 2H), 3.18-3.13 (m, 1H), 2.47-2.38 (m, 2H),1.98-1.94 (m, 2H), 1.24-1.22 (d, J=6.4 Hz, 6H). LC-MS (m/z) 411.2 (MH⁺);t_(R)=2.07 (Method B).

Example 10:5-[(3-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-3-fluorobenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.16 (s, 1H), 7.25 (m, 1H), 6.93 (d, J=7.6 Hz,2H), 6.81 (d, J=9.6 Hz, 1H), 6.27 (s, 1H), 5.36 (br.s, 2H), 4.44-4.38(m, 1H), 4.16 (d, J=9.2 Hz, 2H), 3.57 (t, J=11.6 Hz, 2H), 2.41-2.37 (m,5H), 1.94 (d, J=12.8 Hz, 2H). LC-MS (m/z) 342.2 (MH⁺); t_(R)=2.35(Method C).

Example 11:5-[(2-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-2-fluorobenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.16 (s, 1H), 7.23-7.21 (m, 1H), 7.08-6.94 (m,3H), 6.27 (s, 1H), 5.42 (s, 2H), 4.41 (t, J=11.6 Hz, 1H), 4.16 (d, J=9.6Hz, 2H), 3.57 (t, J=12.0 Hz, 2H), 2.41-2.34 (m, 5H), 1.94 (d, J=12.0 Hz,2H). LC-MS (m/z) 342.2 (MH⁺); t_(R)=2.36 (Method C).

Example 12:5-[(4-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-4-chlorobenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.16 (s, 1H), 7.27 (d, J=7.2 Hz, 2H), 7.09 (d,J=8.4 Hz, 2H), 6.26 (s, 1H), 5.33 (br. s, 2H), 4.44-4.37 (m, 1H), 4.16(dd, J=11.6 Hz, J=3.6 Hz, 2H), 3.57 (t, J=12.0 Hz, 2H), 2.42-2.34 (m,5H), 1.94 (dd, J=12.8 Hz, J=2.4 Hz, 2H). LC-MS (m/z) 358.1 (MH⁺);t_(R)=2.52 (Method C).

Example 13:5-benzyl-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand (bromomethyl)benzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.18 (s, 1H), 7.30-7.26 (m, 3H), 7.16 (m, 2H),6.26 (s, 1H), 5.40 (br. s, 2H), 4.42 (m, 1H), 4.17 (d, J=10.8 Hz, 2H),3.58 (t, J=10.8 Hz, 2H), 2.36 (m, 5H), 1.96 (d, J=13.2 Hz, 2H). LC-MS(m/z) 324.2 (MH⁺); t_(R)=2.11 (Method C).

Example 14:5-[(3-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-3-chlorobenzene.

¹H NMR (CDCl3 400 MHz): δ 8.20-8.18 (m, 1H), 7.29-7.24 (m, 2H),7.15-7.13 (m, 1H), 7.05 (s, 1H), 6.31-6.28 (m, 1H), 5.36 (br. s, 2H),4.45-4.40 (m, 1H), 4.18 (d, J=8.0 Hz, 2H), 3.61-3.56 (m, 2H), 2.40-2.35(m, 5H), 1.97 (m, 2H). LC-MS (m/z) 358.2 (MH⁺); t_(R)=2.29 (Method C).

Example 15:5-[(4-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-4-fluorobenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.17 (s, 1H), 7.16-7.13 (m, 2H), 6.99 (t,J=8.4 Hz, 2H), 6.27 (s, 1H), 5.35 (br. s, 2H), 4.44-4.39 (m, 1H), 4.17(d, J=9.2 Hz, 2H), 3.58 (t, J=12.0 Hz, 2H), 2.42-2.36 (m, 5H), 1.95 (d,J=12.4 Hz, 2H). LC-MS (m/z) 342.2 (MH⁺); t_(R)=2.16 (Method C).

Example 16:6-methyl-5-(p-tolylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 1-(bromomethyl)-4-methylbenzene.

¹H NMR (CDCl₃ 400 MHz): δ 8.18 (s, 1H), 7.12-7.04 (m, 4H), 6.24 (s, 1H),5.35 (br. s, 2H), 4.41 (m, 1H), 4.17 (d, J=9.6 Hz, 2H), 3.58 (t, J=12.0Hz, 2H), 2.42-2.31 (m, 8H), 1.95 (d, J=12.8 Hz, 2H). LC-MS (m/z) 338.2(MH⁺); t_(R)=2.04 (Method B).

Example 17:5-(1,3-benzodioxol-5-ylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 5-(bromomethyl)benzo[d][1,3]dioxole.

¹H NMR (CDCl₃400 MHz): δ 8.16 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.66-6.62(m, 2H), 6.25 (s, 1H), 5.92 (s, 2H), 5.28 (s, 2H), 4.44-4.38 (m, 1H),4.18-4.15 (m, 2H), 3.60-3.55 (m, 2H), 2.43-2.32 (m, 5H), 1.96-1.93 (m,2H). LC-MS (m/z) 368.2 (MH⁺); t_(R)=2.26 (Method C).

Example 18:5-[(6-methoxy-3-pyridyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-oneand 5-(chloromethyl)-2-methoxypyridine.

¹H NMR (CDCl₃ 400 MHz): δ 8.15 (s, 1H), 8.01 (s, 1H), 7.51-7.49 (m, 1H),6.68 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 5.29 (s, 2H), 4.42-4.36 (m, 1H),4.17-4.14 (m, 2H), 3.89 (s, 3H), 3.59-3.53 (m, 2H), 2.40-2.30 (m, 5H),1.94-1.91 (m, 2H). LC-MS (m/z) 355.2 (MH⁺); t_(R)=1.84 (Method B).

Example 19:5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

Triethylamine (198 mg, 0.27 mL, 2.0 mmol) was added to4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde(100 mg, 0.34 mmol) and (tetrahydro-2H-pyran-4-yl)hydrazinedihydrochloride (65 mg, 0.34 mmol) in ethanol (2.5 mL). The reactionmixture was heated by microwave irradiation (130° C. for 30 minutes then150° C. for 20 minutes). The reaction mixture was concentrated in vacuo.The crude material was purified via flash chromatography on silica gel(using a gradient of heptane and ethyl acetate) to give5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(9 mg, 7% yield).

¹H NMR (DMSO d₆ 600 MHz) δ 8.07 (s, 1H), 7.05 (d, J=8.6 Hz, 2H), 6.88(d, J=8.7 Hz, 2H), 6.73 (s, 1H), 5.25 (bs, 2H), 4.71-4.64 (m, 1H), 3.99(dd, J=11.3, 4.1 Hz, 2H), 3.71 (s, 3H), 3.50 (dd, J=11.8, 10.7 Hz, 2H),2.33 (s, 3H), 2.08 (qd, J=12.6, 4.8 Hz, 2H), 1.85 (dd, J=12.5, 2.4 Hz,2H). LC-MS (m/z) 354.1 (MH⁺); t_(R)=0.59 (Method D).

The following compounds were prepared in a similar manner:

Example 20:5-(4-methoxybenzyl)-6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand propylhydrazine.

¹H NMR (DMSO d₆ 600 MHz) δ 8.04 (s, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.88(d, J=8.7 Hz, 2H), 6.65 (s, 1H), 5.24 (bs, 2H), 4.19 (t, J=6.9 Hz, 2H),3.71 (s, 3H), 2.32 (s, 3H), 1.80 (h, J=7.2 Hz, 2H), 0.82 (t, J=7.4 Hz,3H). LC-MS (m/z) 312 (MH⁺); t_(R)=0.65 (Method E).

Example 21:1-isopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand isopropylhydrazine hydrochloride.

¹H NMR (CDCl₃ 400 MHz): δ 8.16 (s, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.82 (d,J=8.4 Hz, 2H), 6.20 (s, 1H), 5.30 (br.s, 2H), 4.61-4.54 (m, 1H), 3.76(s, 3H), 2.35 (s, 3H), 1.54 (d, J=6.8 Hz, 6H). LC-MS (m/z) 312.1 (MH⁺);t_(R)=2.52 (Method C).

Example 22:5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand (tetrahydrofuran-3-yl)hydrazine hydrochloride.

¹H NMR (CDCl₃ 400 MHz): δ 8.23-8.15 (m, 1H), 7.09-7.06 (m, 2H), 6.81 (d,J=8.4 Hz, 2H), 6.37-6.26 (m, 1H), 5.29-5.26 (m, 2H), 5.09-5.02 (m, 1H),4.25-4.12 (m, 3H), 3.97-3.95 (m, 1H), 3.75 (s, 3H), 2.56-2.30 (m, 5H).LC-MS (m/z) 340.2 (MH⁺); t_(R)=2.24 (Method C).

Example 23:1-cyclopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand cyclopropylhydrazine hydrochloride.

¹H NMR (CDCl₃ 400 MHz): δ 8.09 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.82 (d,J=8.4 Hz, 2H), 6.36 (s, 1H), 5.31 (s, 2H), 3.77 (s, 3H), 3.44-3.49 (m,1H), 2.37 (s, 3H), 1.09-1.20 (m, 4H). LC-MS (m/z) 310.2 (MH⁺);t_(R)=2.16 (Method B).

Example 24:1-ethyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand ethylhydrazine oxalate.

¹H NMR (CDCl₃ 400 MHz): δ 8.15 (s, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.83 (d,J=8.4 Hz, 2H), 6.19 (s, 1H), 5.32 (br. s, 2H), 4.24 (q, J=7.6 Hz, 2H),3.77 (s, 3H), 2.37 (s, 3H), 1.49 (t, J=7.6 Hz, 3H). LC-MS (m/z) 298.2(MH⁺); t_(R)=2.33 (Method C).

Example 25:5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydropyran-3-yl-pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand (tetrahydro-2H-pyran-3-yl)hydrazine hydrochloride.

¹H NMR (CDCl₃ 400 MHz): δ 8.15 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.81 (d,J=8.4 Hz, 2H), 6.22 (s, 1H), 5.30 (br. s, 2H), 4.31-4.29 (m, 1H),4.03-3.98 (m, 2H), 3.76 (s, 4H), 3.52-3.46 (m, 1H), 2.36-2.28 (m, 4H),2.19-2.16 (m, 1H), 1.86 (m, 2H). LC-MS (m/z) 354.2 (MH⁺); t_(R)=2.18(Method B).

Example 26:5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(trans)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand trans-(2-methyltetrahydrofuran-3-yl)hydrazine hydrochloride

¹H NMR (CDCl₃ 400 MHz): δ 8.20 (s, 1H), 7.11 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.21 (s, 1H), 5.33 (br. s, 2H), 4.44-4.40 (m, 1H),4.24-4.14 (m, 3H), 3.78 (s, 3H), 2.57-2.47 (m, 2H), 2.38 (s, 3H), 1.32(d, J=5.6 Hz, 3H). LC-MS (m/z) 354.2 (MH⁺); t_(R)=2.37 (Method C).

Example 27:5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(cis)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one

Prepared from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand cis-(2-methyltetrahydrofuran-3-yl)hydrazine hydrochloride

¹H NMR (CDCl₃ 400 MHz): δ 8.18 (s, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.82 (d,J=8.4 Hz, 2H), 6.21 (s, 1H), 5.37-5.23 (m, 2H), 4.90 (bs, 1H), 4.41-4.39(m, 1H), 4.09-4.06 (m, 1H), 3.88-3.82 (m, 1H), 3.76 (s, 3H), 2.64-2.56(m, 2H), 2.36 (s, 3H), 0.84 (d, J=6.0 Hz, 3H). LC-MS (m/z) 354.2 (MH⁺);t_(R)=2.28 (Method C).

Example 28:5-(4-methoxybenzyl)-6-methyl-1-(oxetan-3-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

A mixture of5-(4-methoxybenzyl)-6-methyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(30 mg, 0.111 mmol), 3-iodooxetane (41 mg, 0.223 μmol) and Cs₂CO₃ (109mg, 334 mmol) in DMF (3 mL) was stirred at 100° C. for 1 hour undermicrowave irradiation. The mixture was filtered and purified by basicpreparative HPLC followed by purification by SFC to give5-(4-methoxybenzyl)-6-methyl-1-(oxetan-3-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one(35 mg, 36% yield).

¹H NMR (CDCl₃ 400 MHz): δ 8.23 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.81 (d,J=8.4 Hz, 2H), 6.31 (s, 1H), 5.59-5.52 (m, 1H), 5.31 (br.s, 2H), 5.21(t, J=6.4 Hz, 2H), 5.08 (t, J=7.6 Hz, 2H), 3.76 (s, 3H), 2.37 (s, 3H).LC-MS: t_(R)=2.080 min (Method C), m/z=326.1 [M+H]⁺.

SFC method: Instrument: SFC-13; Column: Chiralpak AS (250 mm×30 mm, 5um); Mobile phase: Base-ETOH=40/60 at 40 mL/min; Column Temp: 38° C.;Nozzle Pressure: 100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 20° C.;Trimmer Temp: 25° C.

Example 29:5-(4-methoxybenzyl)-6-methyl-1-(4-methyltetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one

Prepared as example 19 from4-chloro-1-(4-methoxybenzyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehydeand (4-methyltetrahydro-2H-pyran-4-yl)hydrazine hydrochloride.

¹H NMR (CDCl₃ 400 MHz): δ 8.16 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.8 Hz, 2H), 6.35 (s, 1H), 5.32 (s, 2H), 3.78-3.71 (m, 7H), 2.67-2.63(m, 2H), 2.37 (s, 3H), 2.05-2.03 (m, 2H), 1.62 (s, 3H). LC-MS (m/z)368.2 (MH⁺); t_(R)=2.23 (Method C).

In Vitro Testing PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wasperformed in 60 μL samples containing a fixed amount of the PDE1 enzyme(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA,15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactionswere initiated by addition of the cyclic nucleotide substrate, andreactions were allowed to proceed for 1 hr at room temperature beforebeing terminated through mixing with 20 μL (0.2 mg) yttrium silicate SPAbeads (PerkinElmer). The beads were allowed to settle for 1 hr in thedark before the plates were counted in a Wallac 1450 Microbeta counter.The measured signals were converted to activity relative to anuninhibited control (100%) and IC₅₀ values were calculated using XIFit(model 205, IDBS).

PDE9 Inhibition Assay

A PDE9 assay may for example, be performed as follows: The assay isperformed in 60 μL samples containing a fixed amount of the relevant PDEenzyme (sufficient to convert 20-25% of the cyclic nucleotidesubstrate), a buffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20),0.1 mg/ml BSA, 225 pCi of ³H-labelled cyclic nucleotide substrate,tritium labeled cAMP to a final concentration of 5 nM and varyingamounts of inhibitors. Reactions are initiated by addition of the cyclicnucleotide substrate, and reactions are allowed to proceed for one hr atroom temperature before being terminated through mixing with 15 μL 8mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed tosettle for one hr in the dark before the plates are counted in a Wallac1450 Microbeta counter. The measured signal can be converted to activityrelative to an uninhibited control (100%) and IC₅₀ values can becalculated using the Xlfit extension to EXCEL.

In the context of the present invention the assay was performed in 60 uLassay buffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20) containingenough PDE9 to convert 20-25% of 10 nM ³H-cAMP and varying amounts ofinhibitors. Following 1 hr incubation the reactions were terminated byaddition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). Thebeads were allowed to settle for one hr in the dark before the plateswere counted in a Wallac 1450 Microbeta counter.

1. A compound of formula (I):

wherein: Y is N or CH; R₁ is selected from the group consisting oflinear or branched C₂-C₈ alkyl, saturated monocyclic C₃-C₈ cycloalkyl,oxetanyl, tetrahydrofuranyl and tetrathydropyranyl; all of which can besubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine, hydroxy, cyano andmethoxy; R₂ is: (a) selected from the group consisting of linear orbranched C₁-C₈ alkyl, phenyl, benzo[1,3]dioxole and saturated monocyclicC₃-C₈ cycloalkyl; or (b) phenyl substituted one or more times with oneor more substituents selected from the group consisting of halogen,C₁-C₃ alkyl and methoxy; or (c) pyridyl substituted with a substituentselected from the group consisting of halogen, C₁-C₃ alkyl, C₁-C₃alkoxy, C₁-C₃ fluoroalkoxy, C₃-C₄ cycloalkoxy and C₄-C₅methylcycloalkoxy; or (d) selected from the group consisting of5-membered heteroaryls substituted with C₁-C₃ alkyl; and R₃ is selectedfrom the group consisting of linear or branched C₁-C₃ alkyl andsaturated monocyclic C₃-C₅ cycloalkyl; which can each be optionallysubstituted with a substituent selected from halogen, C₁-C₃ alkoxy,phenyl, dialkylamine and oxetane; or a tautomer or pharmaceuticallyacceptable salt thereof.
 2. The compound or tautomer or pharmaceuticallyacceptable salt thereof of claim 1, wherein Y is N.
 3. The compound ortautomer or pharmaceutically acceptable salt thereof of claim 1, whereinY is CH.
 4. The compound or tautomer or pharmaceutically acceptable saltthereof of claim 1, wherein R₁ is a linear or branched C₂-C₈ alkyl or asaturated monocyclic C₃-C₈ cycloalkyl.
 5. The compound or tautomer orpharmaceutically acceptable salt thereof of claim 1, wherein R₁ isoxetanyl, tetrahydrofuranyl or tetrathydropyranyl.
 6. The compound ortautomer or pharmaceutically acceptable salt thereof of claim 1, whereinR₂ is: (a) phenyl optionally substituted one or more times with one ormore substituents selected from the group consisting of methyl, methoxy,fluorine and chlorine; or (b) pyridyl substituted with a substituentselected from the group consisting of methyl, methoxy, fluorine andchlorine.
 7. The compound or tautomer or pharmaceutically acceptablesalt thereof of claim 1, wherein R₂ is a saturated monocyclic C₃-C₈cycloalkyl.
 8. The compound or tautomer or pharmaceutically acceptablesalt thereof of claim 1, wherein R₃ is C₁₋₃ alkyl.
 9. The compound ortautomer or pharmaceutically acceptable salt thereof of claim 1, whereinR₃ is methyl substituted with a phenyl.
 10. The compound or tautomer orpharmaceutically acceptable salt thereof of claim 1, wherein R₃ ismethyl substituted with a methoxy or oxetane.
 11. The compound ortautomer or pharmaceutically acceptable salt thereof of claim 1,wherein: R₂ is: (a) selected from the group consisting of phenyl,benzo[1,3]dioxole, and saturated monocyclic C₃-C₈ cycloalkyl; or (b)phenyl substituted one or more times with one or more substituentsselected from the group consisting of halogen, C₁-C₃ alkyl and C₁-C₃alkoxy; or (c) pyridyl substituted with a substituent selected from thegroup consisting of halogen, C₁-C₃ alkyl and C₁-C₃ alkoxy, C₁-C₃fluoroalkoxy, C₃-C₄ cycloalkoxy and C₄-C₅ methylcycloalkoxy; and R₃ isC₁-C₃ alkyl which can each be optionally substituted with a substituentselected from the group consisting of halogen, C₁-C₃ alkoxy, phenyl andoxetane.
 12. The compound or tautomer or pharmaceutically acceptablesalt thereof of claim 1, wherein the compound is selected from the groupconsisting of:6-benzyl-5-(cyclohexylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one;5-(cyclohexylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one;5-(cyclohexylmethyl)-6-methyl-1-propyl-pyrazolo[3,4-d]pyrimidin-4-one;6-ethyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;6-(methoxymethyl)-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;6-isopropyl-5-[(4-methoxyphenyl)methyl]-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;5-[(4-methoxyphenyl)methyl]-6-(oxetan-3-ylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[3,4-d]pyrimidin-4-one;5-[(3-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(2-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(4-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-benzyl-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(3-chlorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(4-fluorophenyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;6-methyl-5-(p-tolylmethyl)-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-(1,3-benzodioxol-5-ylmethyl)-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(6-methoxy-3-pyridyl)methyl]-6-methyl-1-tetrahydropyran-4-yl-pyrazolo[4,3-c]pyridin-4-one;5-(4-methoxybenzyl)-6-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one;5-(4-methoxybenzyl)-6-methyl-1-propyl-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one;1-isopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydrofuran-3-yl-pyrazolo[4,3-c]pyridin-4-one;1-cyclopropyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one;1-ethyl-5-[(4-methoxyphenyl)methyl]-6-methyl-pyrazolo[4,3-c]pyridin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-tetrahydropyran-3-yl-pyrazolo[4,3-c]pyridin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(2S,3R)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-[(2R,3R)-2-methyltetrahydrofuran-3-yl]pyrazolo[4,3-c]pyridin-4-one;5-[(4-methoxyphenyl)methyl]-6-methyl-1-(oxetan-3-yl)pyrazolo[4,3-c]pyridin-4-one;and5-(4-methoxybenzyl)-6-methyl-1-(4-methyltetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one.13. A pharmaceutical composition comprising a therapeutically effectiveamount of the compound or tautomer or pharmaceutically acceptable saltthereof of claim 1 and one or more pharmaceutically acceptable carriers,diluents and excipients.
 14. A pharmaceutical composition comprising atherapeutically effective amount of the compound or tautomer orpharmaceutically acceptable salt thereof of claim 11 and one or morepharmaceutically acceptable carriers, diluents and excipients.
 15. Apharmaceutical composition comprising a therapeutically effective amountof the compound or tautomer or pharmaceutically acceptable salt thereofof claim 12 and one or more pharmaceutically acceptable carriers,diluents and excipients.
 16. A method for treating a neurodegenerativedisorder or a psychiatric disorder comprising administering atherapeutically effective amount of the pharmaceutical composition ofclaim 13 to a subject in need thereof, wherein said neurodegenerativedisorder is selected from the group consisting of Alzheimer's Disease,Parkinson's Disease and Huntington's Disease, and said psychiatricdisorder is selected from the group consisting of Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,cognitive impairment, cognitive impairment associated with schizophrenia(CIAS), and restless leg syndrome.
 17. A method for treating aneurodegenerative disorder or a psychiatric disorder comprisingadministering a therapeutically effective amount of the pharmaceuticalcomposition of claim 14 to a subject in need thereof, wherein saidneurodegenerative disorder is selected from the group consisting ofAlzheimer's Disease, Parkinson's Disease and Huntington's Disease, andsaid psychiatric disorder is selected from the group consisting ofAttention Deficit Hyperactivity Disorder (ADHD), depression, anxiety,narcolepsy, cognitive impairment, cognitive impairment associated withschizophrenia (CIAS), and restless leg syndrome.
 18. A method fortreating a neurodegenerative disorder or a psychiatric disordercomprising administering a therapeutically effective amount of thepharmaceutical composition of claim 15 to a subject in need thereof,wherein said neurodegenerative disorder is selected from the groupconsisting of Alzheimer's Disease, Parkinson's Disease and Huntington'sDisease, and said psychiatric disorder is selected from the groupconsisting of Attention Deficit Hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, cognitive impairment, cognitiveimpairment associated with schizophrenia (CIAS), and restless legsyndrome.